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Ibrutinib combined with bendamustine and rituximab compared with placebo, bendamustine, and rituximab for previously treated chronic lymphocytic leukaemia or small lymphocytic lymphoma (HELIOS): a randomised, double-blind, phase 3 study
A. Chanan-Khan, P. Cramer, F. Demirkan, G. Fraser, RS. Silva, S. Grosicki, A. Pristupa, A. Janssens, J. Mayer, NL. Bartlett, MS. Dilhuydy, H. Pylypenko, J. Loscertales, A. Avigdor, S. Rule, D. Villa, O. Samoilova, P. Panagiotidis, A. Goy, A....
Language English Country England, Great Britain
Document type Clinical Trial, Phase III, Comparative Study, Journal Article, Randomized Controlled Trial, Research Support, Non-U.S. Gov't
NLK
ProQuest Central
from 2000-09-01 to 2 months ago
Nursing & Allied Health Database (ProQuest)
from 2000-09-01 to 2 months ago
Health & Medicine (ProQuest)
from 2000-09-01 to 2 months ago
Public Health Database (ProQuest)
from 2000-09-01 to 2 months ago
- MeSH
- Intention to Treat Analysis MeSH
- Anemia chemically induced MeSH
- Bendamustine Hydrochloride administration & dosage MeSH
- Leukemia, Lymphocytic, Chronic, B-Cell drug therapy MeSH
- Adult MeSH
- Double-Blind Method MeSH
- Atrial Fibrillation chemically induced MeSH
- Hemorrhage chemically induced MeSH
- Middle Aged MeSH
- Humans MeSH
- Nausea chemically induced MeSH
- Neutropenia chemically induced MeSH
- Retreatment MeSH
- Disease-Free Survival MeSH
- Disease Progression MeSH
- Antineoplastic Combined Chemotherapy Protocols adverse effects therapeutic use MeSH
- Pyrazoles administration & dosage adverse effects MeSH
- Pyrimidines administration & dosage adverse effects MeSH
- Rituximab administration & dosage MeSH
- Aged, 80 and over MeSH
- Aged MeSH
- Thrombocytopenia chemically induced MeSH
- Check Tag
- Adult MeSH
- Middle Aged MeSH
- Humans MeSH
- Male MeSH
- Aged, 80 and over MeSH
- Aged MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Clinical Trial, Phase III MeSH
- Research Support, Non-U.S. Gov't MeSH
- Randomized Controlled Trial MeSH
- Comparative Study MeSH
BACKGROUND: Most patients with chronic lymphocytic leukaemia or small lymphocytic lymphoma relapse after initial therapy. Bendamustine plus rituximab is often used in the relapsed or refractory setting. We assessed the efficacy and safety of adding ibrutinib, an oral covalent inhibitor of Bruton's tyrosine kinase (BTK), to bendamustine plus rituximab in patients with previously treated chronic lymphocytic leukaemia or small lymphocytic lymphoma. METHODS: The HELIOS trial was an international, double-blind, placebo-controlled, phase 3 study in adult patients (≥18 years of age) who had active chronic lymphocytic leukaemia or small lymphocytic lymphoma with measurable lymph node disease (>1·5 cm) by CT scan, and had relapsed or refractory disease following one or more previous lines of systemic therapy consisting of at least two cycles of a chemotherapy-containing regimen, an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1, and adequate bone marrow, liver, and kidney function. Patients with del(17p) were excluded because of known poor response to bendamustine plus rituximab. Patients who had received previous treatment with ibrutinib or other BTK inhibitors, refractory disease or relapse within 24 months with a previous bendamustine-containing regimen, or haemopoietic stem-cell transplant were also excluded. Patients were randomly assigned (1:1) by a web-based system to receive bendamustine plus rituximab given in cycles of 4 weeks' duration (bendamustine: 70 mg/m(2) intravenously on days 2-3 in cycle 1, and days 1-2 in cycles 2-6; rituximab: 375 mg/m(2) on day 1 of cycle 1, and 500 mg/m(2) on day 1 of cycles 2-6 for a maximum of six cycles) with either ibrutinib (420 mg daily orally) or placebo until disease progression or unacceptable toxicity. Patients were stratified according to whether they were refractory to purine analogues and by number of previous lines of therapy. The primary endpoint was independent review committee (IRC)-assessed progression-free survival. Crossover to ibrutinib was permitted for patients in the placebo group with IRC-confirmed disease progression. Analysis was by intention-to-treat and is continuing for further long-term follow-up. The trial is registered with ClinicalTrials.gov, number NCT01611090. FINDINGS: Between Sept 19, 2012, and Jan 21, 2014, 578 eligible patients were randomly assigned to ibrutinib or placebo in combination with bendamustine plus rituximab (289 in each group). The primary endpoint was met at the preplanned interim analysis (March 10, 2015). At a median follow-up of 17 months (IQR 13·7-20·7), progression-free survival was significantly improved in the ibrutinib group compared with the placebo group (not reached in the ibrutinib group (95% CI not evaluable) vs 13·3 months (11·3-13·9) in the placebo group (hazard ratio [HR] 0·203, 95% CI 0·150-0·276; p<0·0001). IRC-assessed progression-free survival at 18 months was 79% (95% CI 73-83) in the ibrutinib group and 24% (18-31) in the placebo group (HR 0·203, 95% CI 0·150-0·276; p<0·0001). The most frequent all-grade adverse events were neutropenia and nausea. 222 (77%) of 287 patients in the ibrutinib group and 212 (74%) of 287 patients in the placebo group reported grade 3-4 events; the most common grade 3-4 adverse events in both groups were neutropenia (154 [54%] in the ibrutinib group vs 145 [51%] in the placebo group) and thrombocytopenia (43 [15%] in each group). A safety profile similar to that previously reported with ibrutinib and bendamustine plus rituximab individually was noted. INTERPRETATION: In patients eligible for bendamustine plus rituximab, the addition of ibrutinib to this regimen results in significant improvements in outcome with no new safety signals identified from the combination and a manageable safety profile. FUNDING: Janssen Research & Development.
1st Department of Propedeutic Medicine University of Athens Athens Greece
Center for CLL University of Pennsylvania Philadelphia PA USA
Department 1 of Internal Medicine and German CLL Study Group University of Cologne Cologne Germany
Department of Cancer Prevention Faculty of Public Health Silesian Medical University Katowice Poland
Department of Haematology Derriford Hospital Plymouth UK
Department of Hematology Cherkassy Regional Oncological Center Cherkassy Ukraine
Department of Hematology Fundaleu Buenos Aires Argentina
Division of Hematology Dokuz Eylul University Izmir Turkey
Division of Medical Oncology British Columbia Cancer Agency Vancouver BC Canada
Hematology Department Hospital Universitario La Princesa IIS IP Madrid Spain
Hôpital Haut Lévêque Bordeaux Pessac France
IEP São Lucas Hemomed Oncologia e Hematologia São Paulo Brazil
Janssen Research and Development High Wycombe UK
Janssen Research and Development Raritan NJ USA
Janssen Research and Development Spring House PA USA
John Theurer Cancer Center at Hackensack University Medical Center Hackensack NJ USA
Juravinski Cancer Centre McMaster University Hamilton ON Canada
Mayo Clinic Cancer Center Jacksonville FL USA
Nizhny Novogorod Regional Clinical Hospital Nizhny Novogorod Russia
Regional Clinical Hospital Ryazan Russia
Universitaire Ziekenhuizen Leuven Leuven Belgium
Washington University School of Medicine Siteman Cancer Center St Louis MO USA
References provided by Crossref.org
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